Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][NH2:26])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14]([NH:26][CH2:25][CH2:24][NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:27])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.20 g (0.90 mmol) of N-[(benzyloxy)carbonyl]-beta-alanine and 0.187 g (1.17 mmol) of tert-butyl(2-aminoethyl)carbamate are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.223 g (1.17 mmol) of EDC and 0.036 g (0.27 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[Mn]([O-])(=O)(=O)=[O:17].[K+]>[OH-].[Na+]>[CH3:9][O:8][C:6]1[C:5]([O:10][CH3:11])=[CH:4][C:3]2[S:12](=[O:14])(=[O:13])[NH:15][C:1](=[O:17])[C:2]=2[CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C)c(S(N)(=O)=O)cc1OC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)S(=O)(=O)NC2=O

Procedure:
16 gm (0.08 mol) of 2-methyl-4,5-dimethoxy-benzene sulfonamide were dissolved in 500 ml of an aqueous 5% sodium hydroxide solution, and the solution was heated at its boiling point for 2 hours after addition of 39.6 gm (0.25 mol) of potassium permanganate. After cooling, the reaction mixture was suction-filtered through celite, and the desired product was precipitated by addition of concentrated hydrochloric acid. Rf -value (benzene/acetone = 3/1): 0.2-0.4.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O-:8])=O)[N:3]=[C:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:14][C@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@H:15]([NH:14][C:6]([C:4]3[N:3]=[C:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:1][CH:5]=3)=[O:8])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CCOC(=O)c1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 66.3 %

Procedure:
(R)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from 2,4-thiazoledicarboxylic acid, 2-ethyl ester (0.528 g, 2.62 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.6 g, 2.186 mmol). The product triturated diethyl ether. Yield 66.3%. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (d, 3H), 1.34 (t, 3H), 4.34 (dd, 1H), 4.39-4.47 (m, 3H), 4.47-4.56 (m, 1H), 6.94 (d, 1H), 7.83 (d, 1H), 7.95-7.96 (m, 2H), 8.02 (dd, 1H), 8.55 (s, 1H), 8.61 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]=[C:16]=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18]([C:20]1([CH2:35][CH3:36])[C:23](=[O:24])[NH:22][CH:21]1[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[CH3:19].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:35]([C:20]1([CH2:18][CH3:19])[C:23](=[O:24])[N:22]([C:16]([NH:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:21]1[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[CH3:36]
Reactant: O=C=NCc1ccccc1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC1(CC)C(=O)N(C(=O)NCc2ccccc2)C1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Triethylamine (1.26 mL, 9.1 mmol), 4-dimethylaminopyridine (20 mg, 0.2 mmol), and benzyl isocyanate (1.12 mL, 9.1 mmol) were successively added to a solution of 4-(3,3-diethyl-4-oxo-2-azetidinyl)oxy-nitrobenzene (1.2 gm, 4.6 mmol) in methylene chloride (10 mL). The solution was stirred at room temperature for 1.5 hours, then ethyl acetate (100 mL) was added. The solution was sucessively washed with 1N hydrochloric acid (3×20 mL), 1N sodium bicarbonate solution (3×20 mL), water (20 mL), and saturated salt solution (20 mL), 1N sodium solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 15% ethyl acetate in hexanes and recrystallized from ethyl acetate/hexanes as a white solid (mp. 96°-97° C.; 1.3 gm, 70% yield): 1H-NMR δ (CDCl3) 1.04 (3H, t, J=7 hz), 1.08 (3H, t, J=7 Hz), 1.76-2.10 (4H, m), 4.47 (2H, d, J=6 hz), 5.76 (1H, s), 7.26-7.44 (7H, m), 8.24 (2H, d, J=9 Hz; ir (thin film) 1780, 1720 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@H:13]3[CH2:14][CH2:15][C@@H:16]([NH:19][CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ccc2c(N[C@H]3CC[C@@H](NCc4cnc5ccccc5c4)CC3)ccnc2c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (40 mg, 0.14 mmol) and 3-quinolinecarboxaldehyde (22 mg, 0.14 mmol) in dichloroethane (0.5 mL) and methanol (0.5 mL) was treated acetic acid (0.018 mg, 0.28 mmol) and MP-cyanoborohydride (100 mg, 0.436 mmol, Argonaut Technologies). The mixture was stirred at 60° C. for 18 hours, filtered, and purified by reverse phase HPLC to provide the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[C:11]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)#N.Cl.[OH-:21].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:19][C:18]1[C:13]([C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[O:21])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1Br
Reactant: [OH-]
Reactant: Cc1cccnc1C#N
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ncccc1C

Procedure:
35.5 g of o-bromoanisole were added dropwise to 5.71 g of magnesium turnings covered with 50 ml of tetrahydrofuran while heating to maintain reflux. 15 minutes after completion of the addition 14.93 g of 2-cyano-3-methylpyridine in 150 ml of tetrahydrofuran were added dropwise without further heating. After 1 hour at room temperature dilute hydrochloric acid and ethyl acetate were added followed by dilute sodium hydroxide solution to pH 14. The mixture was extracted with ethyl acetate, the organic extract was dried over sodium sulphate and then evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and then ethyl acetate/petroleum ether (1:2) for the elution. There were obtained 9.81 g of 2-methoxyphenyl 3-methyl-2-pyridyl ketone in the form of a solid of melting point 98-100° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.I[CH2:25][CH3:26]>>[CH2:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)[CH3:26]
Reactant: CCI
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Product: CCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (E21) was alkylated with iodoethane using the method of Example 22. The title compound was obtained as a white solid (27%), which was converted to its hydrochloride salt and crystallised from acetone/ethanol/ether as a white solid mp 243-245° C.
Reaction SMILES: COC1N=CC([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=CC=1.O=C1CCN([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])CC1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[F:34][C:31]([F:32])([F:33])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][CH2:22][C:21]([NH:20][C@@H:17]1[CH2:18][CH2:19][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:14][CH2:13]2)[CH2:16]1)=[O:36])=[O:35]
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby benzyl 4-oxopiperidine-1-carboxylate was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.30-1.45 (m, 2H), 1.64-1.18 (m, 1H), 1.84-2.00 (m, 2H), 2.08-2.38 (m, 2H), 2.50-2.64 (m, 2H), 2.80-3.00 (m, 4H), 3.20-3.40 (m, 2H), 4.03 (s, 2H), 4.08-4.13 (m, 2H), 4.34-4.44 (m, 1H), 5.12 (s, 2H), 7.35 (m, 5H), 7.70 (t, J=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.22 (s, 1H). MS m/z: 533 (M+1).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH2:23](N)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]CC.C(N(CC)CC)C>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: CCCCCCCCCCCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.5 %

Procedure:
To a stirred yellow solution of VII (290.8 mg, 0.852 mmol) in anhydrous THF (10 mL) was added 1-dodecylamine (174 mg, 1.1×0.852 mmol) and then, dropwise, triethylamine (118 mg, 132 μL, 1.1×0.852 mmol). The solution was stirred for 3.5 hours at room temperature. The colorless solution was then diluted with diethylether and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (6:4, v/v) to give 165 mg (48%) of a white solid, 10: mp=54-56° C. (uncorrected); Rf=0.61 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.99 (d, 3J=8.0 Hz, 1H), 6.95 (d, 4J=1.55 Hz, 1H), 6.92 (bd, 3J=8.0 Hz, 1H), 5.04 (s, 2H), 4.69 (bs, 1H; NH), 3.82 (s, 3H), 3.17 (apparent quartet, 3J=6.7 Hz, 2H), 2.29 (s, 3H), 1.51-1.43 (m, 2H), 1.32-1.19 (m, 18H), and 0.86 (t, 3J=7 Hz, 3H). Exact mass (FAB+) calculated for C23H38NO5 [M+H] 408.2744. found 408.2749.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([NH:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Reactant: NCCN1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)NCCN2CCCCC2)ccn1
Yield: 13.2 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (80.0 mg, 0.24 mmol), 2-piperidine-1-yl-ethylamine (46.2 mg, 0.05 ml, 0.36 mmol), EDC (69.0 mg, 0.36 mmol) and HOBt (48.7 mg, 0.36 mmol) in DMF 4 ml was added DIPEA (46.5 mg, 0.06 ml, 0.36 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC (n-Hexane:EtoAC:MeOH=6:3:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(2-piperidine-1-yl-ethyl)-isonicotinamide as a yellow solid (14.3 mg, 13.3% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[I:11]I.[I-].[K+]>[NH4+].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[I:11]
Reactant: II
Reactant: CC(=O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: CC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 51 %

Procedure:
4.08 g (corresponding to 30.0 mmol) of 4′-hydroxyacetophenone was dissolved in 250 mL of 28% aqueous ammonium solution, and a solution of 7.61 g (corresponding to 30.0 mmol) of iodine and 24.3 g (corresponding to 146 mmol) of potassium iodide in 60 mL of water was added thereto. The resulting solution was stirred at room temperature for 22.5 hours. After the completion of the reaction, the reaction mixture was concentrated, diluted with water, and then extracted three times with ethyl acetate. The combined ethyl acetate layers were washed once with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. To the resulting concentrates, 60 mL of water and 40 mL of 8 mol/L sodium hydroxide solution were added, sufficiently mixed, and filtered to remove insoluble matters. Then, conc. hydrochloric acid was added to the filtrate to make it acidic, and the precipitates were filtered and dried under reduced pressure. The resulted precipitates were dissolved in a mixed solution of chloroform and ethyl acetate, and then water was added thereto, and extracted with chloroform for five times. The combined chloroform layers were dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure, to obtain 4.00 g (corresponding to 15.3 mmol) of 4′-hydroxy-3′-iodoacetophenone (FIG. 3, Step 4).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.ClC1C=C(C([NH:21][C@H:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@H:23]2[O:33][CH2:34][CH2:35][CH3:36])=O)NC=1C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:21][C@@H:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@@H:23]1[O:33][CH2:34][CH2:35][CH3:36])=[O:11]
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543, 1.77 g, 9.13 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73, 2.1 g, 9.13 mmol) in dichloromethane (150 mL) was added N-Hydroxybenzotriazole (1.67 g, 10.95 mmol) and N-methylmorpholine (2.76 g, 27.39 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.023 g, 16.43 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate 3.3 g (89.1%) as solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CCNc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CCNc2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline (16.07 g, 0.098 mol) in dichloromethane (100 mL) at 0° C. were added sequentially triethylamine (16.3 mL, 0.12 mol), tert-butyldiphenylsilylchloride (28.4 g, 0.103 mol) and 4-(dimethylamino)pyridine (0.6 g, 4.9 mmol). After 30 minutes, the solution was warmed to room temperature and stirred for another 2 hours. The reaction mixture was diluted with dichlormethane (200 mL), washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layers were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to provide 22.1 g (56%) of the desired compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1C=O.[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[CH3:24]O>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:24]=[N:23][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCc2ccccc2N1
Reactant: NC1CCCc2ccccc21
Reactant: CO
Product: C(=NC1CCCc2ccccc21)c1cccc2c1NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
0.57 g of tetrahydroquinolino aldehyde was dissolved in 10 ml of methanol and then 0.51 ml of 1,2,3,4-tetrahydro naphthyl amine was slowly added thereto. The resulting mixture was stirred at room temperature overnight before some precipitates were slowly formed. Then, the resulting mixture was filtered while being washed with methanol to provide ivory solids as a clean product (0.72 g). (Yield: 70%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-])=O.[CH3:18]N(C(N(C)C)N(C)C)C.[H][H]>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd]>[O:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:1][CH:18]=[CH:17]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Reactant: CN(C)C(N(C)C)N(C)C
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-nitro-5-phenoxytoluene (1.15 g, 5.0 mmol) and tris(dimethylamino)methane (0.87 g, 6.0 mmol) in 10 mL dry toluene and heat to reflux under nitrogen. After 2 hours, cool the reaction mixture to room temperature and evaporate the toluene under reduced pressure to form a residue. Dissolve the residue in 15 mL EtOAc, mix with Pd/C (10%, 100 mg), stir at room temperature under 1 atmosphere of hydrogen for 1.5 days. Filter off catalyst and concentrate the filtrate. Chromatograph on silica gel eluting with hexanes/EtOAc give the title compound as a solid: 1H NMR (300 MHz, CDCl3) 6.49-6.50 (m, 1H), 6.93-7.03 (m, 4H), 7.22-7.27 (m, 5H), 8.15 (br, 1H).
Reaction SMILES: C[O:2][C:3](=[O:50])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:10][C:9]([C:22](=[O:39])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)=[CH:8][C:7]=1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1.[K+].[Br-]>>[CH2:32]([O:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:22]([C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:6]([O:5][CH2:4][C:3]([OH:50])=[O:2])=[C:7]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:49])[F:47])[CH:41]=2)[CH:8]=1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)COc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCc2cccc(OCc3ccccc3)c2)cc1-c1cccc(C(F)(F)F)c1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)NCc2cccc(OCc3ccccc3)c2)cc1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a white foam (0.286 g, 74%) from [5′-(3-benzyloxy-benzylcarbamoyl)-3 ,3″-bis-trifluoromethyl-[1,1′:3′,1″]terphenyl-2′-yloxy]-acetic acid methyl ester using a procedure similar to step 2 of Example 192. 1H NMR (DMSO-d6) δ 12.60 (bs, 1H); 9.50 (bt, 1H); 8.00-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.44-7.22 (m, 7H), 6.98-6.94 (m, 2H); 5.08 (s, 2H); 4.42 (s, 2H); 3.81 (s, 2H) IR (KBr) 3350, 2950, 1720, 1630, 1610, 1540, 1510, 1460, 1320, 1230, 1210, 1180, 1160, 1120, 1080 cm1; mass spectrum [(−)ESI], m/z 678 (M−H)−; Anal. Calcd. for C37H27F6NO5: C, 65.39; H, 4.00; N, 2.06, Found: C, 63.35; H, 4.31; N, 2.59
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].CO.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of tert-butyl 3-(aminomethyl)benzylcarbamate (0.80 g, 3.39 mmol) in methanol (0.11 g, 3.39 mmol) was added 4-(trifluoromethyl)benzaldehyde (0.45 mL, 3.39 mmol) under nitrogen. The reaction mixture was stirred for 10 min, followed by the addition of sodium triacetoxyborohydride (1.08 g, 5.08 mmol). The resulting mixture was stirred at rt. for 20 h. To the reaction mixture was added 1 N HCl solution and the mixture was concentrated. The residue was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO4, and concentrated to give an oil. The sample was purified by silica gel flash chromatography. Elution with dichloromethane to 30% of ethyl acetate in dichloromethane gave a colorless oil (0.64 g, 47%). 1H NMR (CDCl3): δ 7.61 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.33-7.22 (m, 4H), 4.34 (m, 2H), 3.89 (s, 2H), 3.82 (s, 2H), 1.48 (s, 9H); MS (ESI): (M+H)+=395.4.